Proteins involved in repression of the human
beta-globin gene may be useful in the treatment of
sickle cell anemia, in conjunction with
therapy to reactivate fetal
globin genes. If there is a reciprocal elevation of
gamma-globin expression upon repression, this approach could be useful in additional
hemoglobinopathies. We previously showed that repression of the
beta-globin gene appears to be mediated through two DNA sequences, silencers I and II, and identified a
protein termed BP1 which binds to both silencer sequences. In this study, we cloned two cDNAs encoding
proteins which bind to an
oligonucleotide in silencer I containing a BP1 binding site. These cDNAs correspond to HMG-I and HMG-Y,
isoforms regarded as architectural
proteins. We demonstrate that binding of HMG-I(Y) to this
oligonucleotide causes bending/flexure of the
DNA. HMG-I(Y) also binds to a second
oligonucleotide containing a BP1 binding site located in a negative control region upstream of the
delta-globin gene, suggesting a role for HMG-I(Y) in repression of adult
globin genes. Expression studies revealed that HMG-I(Y) is ubiquitously expressed in human tissues that do not express
beta-globin, being present in 48 of 50 tissues and six hematopoietic cell lines examined. Furthermore, HMG-I(Y) expression is down-regulated during differentiation of primary erythroid cells. We present a model in which HMG-I(Y) alters DNA conformation to allow binding of
repressor proteins, and in which the relative amount of HMG-I(Y) helps to determine the repressive state of the
beta-globin gene.